Details
| Original language | English |
|---|---|
| Article number | 2083 |
| Journal | Nature Communications |
| Volume | 8 |
| Issue number | 1 |
| Publication status | Published - 1 Dec 2017 |
| Externally published | Yes |
Abstract
Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels-Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2-sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Biochemistry, Genetics and Molecular Biology(all)
- General Biochemistry,Genetics and Molecular Biology
- Physics and Astronomy(all)
- General Physics and Astronomy
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In: Nature Communications, Vol. 8, No. 1, 2083, 01.12.2017.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - A modular synthesis of tetracyclic meroterpenoid antibiotics
AU - Wildermuth, Raphael
AU - Speck, Klaus
AU - Haut, Franz Lucas
AU - Mayer, Peter
AU - Karge, Bianka
AU - Brönstrup, Mark
AU - Magauer, Thomas
N1 - Funding Information: T.M. acknowledges the German Research Foundation (Emmy Noether Project MA5999/ 2-1), the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement No 714049) and the Funds of the Chemical Industry (Sachkostenzuschuss and Dozentenpreis). We thank Dr. Kevin Mellem (Revolution Medicines) and Dr. Bryan Matsuura (LMU Munich) for helpful discussions.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels-Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2-sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.
AB - Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels-Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2-sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.
UR - http://www.scopus.com/inward/record.url?scp=85037996037&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-02061-7
DO - 10.1038/s41467-017-02061-7
M3 - Article
C2 - 29234008
AN - SCOPUS:85037996037
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2083
ER -